scholarly journals Influence of T Cell-Mediated Immune Surveillance on Somatic Mutation Occurrences in Melanoma

2022 ◽  
Vol 12 ◽  
Author(s):  
Chongming Jiang ◽  
Evelien Schaafsma ◽  
Wei Hong ◽  
Yanding Zhao ◽  
Ken Zhu ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Mhc Class I ◽  
Somatic Mutations ◽  
Immune Surveillance ◽  
Human Leukocyte ◽  
The Cancer Genome Atlas ◽  
Class I ◽  
Leukocyte Antigen ◽  
Recurrent Mutations ◽  
Cancer Genome Atlas

BackgroundNeoantigens are presented on the cancer cell surface by peptide-restricted human leukocyte antigen (HLA) proteins and can subsequently activate cognate T cells. It has been hypothesized that the observed somatic mutations in tumors are shaped by immunosurveillance.MethodsWe investigated all somatic mutations identified in The Cancer Genome Atlas (TCGA) Skin Cutaneous Melanoma (SKCM) samples. By applying a computational algorithm, we calculated the binding affinity of the resulting neo-peptides and their corresponding wild-type peptides with the major histocompatibility complex (MHC) Class I complex. We then examined the relationship between binding affinity alterations and mutation frequency.ResultsOur results show that neoantigens derived from recurrent mutations tend to have lower binding affinities with the MHC Class I complex compared to peptides from non-recurrent mutations. Tumor samples harboring recurrent SKCM mutations exhibited lower immune infiltration levels, indicating a relatively colder immune microenvironment.ConclusionsThese results suggested that the occurrences of somatic mutations in melanoma have been shaped by immunosurveillance. Mutations that lead to neoantigens with high MHC class I binding affinity are more likely to be eliminated and thus are less likely to be present in tumors.

scholarly journals Human Leukocyte Antigen Susceptibility Map for Severe Acute Respiratory Syndrome Coronavirus 2

2020 ◽  
Vol 94 (13) ◽  
Author(s):  
Austin Nguyen ◽  
Julianne K. David ◽  
Sean K. Maden ◽  
Mary A. Wood ◽  
Benjamin R. Weeder ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Human Leukocyte Antigen ◽  
Mhc Class I ◽  
Human Leukocyte ◽  
Viral Disease ◽  
Hla Typing ◽  
Class I ◽  
Susceptibility Map ◽  
Leukocyte Antigen ◽  
Human Coronaviruses

ABSTRACT Genetic variability across the three major histocompatibility complex (MHC) class I genes (human leukocyte antigen A [HLA-A], -B, and -C genes) may affect susceptibility to and severity of the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19). We performed a comprehensive in silico analysis of viral peptide-MHC class I binding affinity across 145 HLA-A, -B, and -C genotypes for all SARS-CoV-2 peptides. We further explored the potential for cross-protective immunity conferred by prior exposure to four common human coronaviruses. The SARS-CoV-2 proteome was successfully sampled and was represented by a diversity of HLA alleles. However, we found that HLA-B*46:01 had the fewest predicted binding peptides for SARS-CoV-2, suggesting that individuals with this allele may be particularly vulnerable to COVID-19, as they were previously shown to be for SARS (M. Lin, H.-T. Tseng, J. A. Trejaut, H.-L. Lee, et al., BMC Med Genet 4:9, 2003, https://bmcmedgenet.biomedcentral.com/articles/10.1186/1471-2350-4-9). Conversely, we found that HLA-B*15:03 showed the greatest capacity to present highly conserved SARS-CoV-2 peptides that are shared among common human coronaviruses, suggesting that it could enable cross-protective T-cell-based immunity. Finally, we reported global distributions of HLA types with potential epidemiological ramifications in the setting of the current pandemic. IMPORTANCE Individual genetic variation may help to explain different immune responses to a virus across a population. In particular, understanding how variation in HLA may affect the course of COVID-19 could help identify individuals at higher risk from the disease. HLA typing can be fast and inexpensive. Pairing HLA typing with COVID-19 testing where feasible could improve assessment of severity of viral disease in the population. Following the development of a vaccine against SARS-CoV-2, the virus that causes COVID-19, individuals with high-risk HLA types could be prioritized for vaccination.

scholarly journals Targeting the coding sequence: opposing roles in regulating classical and non-classical MHC class I molecules by miR-16 and miR-744

2020 ◽  
Vol 8 (1) ◽  
pp. e000396
Author(s):  
Michael Friedrich ◽  
Christoforos K Vaxevanis ◽  
Katharina Biehl ◽  
Anja Mueller ◽  
Barbara Seliger
Keyword(s):  
Mhc Class I ◽  
Binding Sites ◽  
Hla Class I ◽  
The Cancer Genome Atlas ◽  
Class I ◽  
Atlas Data ◽  
Candidate Mirnas ◽  
Cancer Genome Atlas ◽  
Mhc Class I Molecules ◽  
Genome Atlas

BackgroundTo control gene expression, microRNAs (miRNAs) are of key importance and their deregulation is associated with the development and progression of various cancer types. In this context, a discordant messenger RNA/protein expression pointing to extensive post-transcriptional regulation of major histocompatibility complex (MHC) class I molecules was already shown. However, only a very limited number of miRNAs targeting these molecules have yet been identified. Despite an increasing evidence of coding sequence (CDS)-located miRNA binding sites, there exists so far, no detailed study of the interaction of miRNAs with the CDS of MHC class I molecules.MethodsUsing an MS2-tethering approach in combination with small RNA sequencing, a number of putative miRNAs binding to the CDS of human leukocyte antigen (HLA)-G were identified. These candidate miRNAs were extensively screened for their effects in the HLA-G-positive JEG3 cell line. Due to the high sequence similarity between HLA-G and classical MHC class I molecules, the impact of HLA-G candidate miRNAs on HLA class I surface expression was also analyzed. The Cancer Genome Atlas data were used to correlate candidate miRNAs and HLA class I gene expression.ResultsTransfection of candidate miRNAs revealed that miR-744 significantly downregulates HLA-G protein levels. In contrast, overexpression of the candidate miRNAs miR-15, miR-16, and miR-424 sharing the same seed sequence resulted in an unexpected upregulation of HLA-G. Comparable results were obtained for classical MHC class I members after transfection of miRNA mimics into HEK293T cells. Analyses of The Cancer Genome Atlas data sets for miRNA and MHC class I expression further validated the results.ConclusionsOur data expand the knowledge about MHC class I regulation and showed for the first time an miRNA-dependent control of MHC class I antigens mediated by the CDS. CDS-located miRNA binding sites could improve the general use of miRNA-based therapeutic approaches as these sites are highly independent of structural variations (e.g. mutations) in the gene body. Surprisingly, miR-16 family members promoted MHC class I expression potentially in a gene activation-like mechanism.

Induction of cytotoxic T-cell responses against immunoglobulin V region–derived peptides modified at human leukocyte antigen–A2 binding residues

Blood ◽  
2001 ◽  
Vol 98 (10) ◽  
pp. 2999-3005 ◽  
Author(s):  
Sabine Harig ◽  
Mathias Witzens ◽  
Angela M. Krackhardt ◽  
Andreas Trojan ◽  
Patrick Barrett ◽  
...  
Keyword(s):  
Amino Acid ◽  
Human Leukocyte Antigen ◽  
Binding Affinity ◽  
Mhc Class I ◽  
Human Leukocyte ◽  
Leukocyte Antigen ◽  
Native Peptide ◽  
Binding Residues ◽  
V Region ◽  
Heteroclitic Peptides

Abstract Cytotoxic T-lymphocyte (CTL) responses can be generated against peptides derived from the immunoglobulin (Ig) V region in some but not all patients. The main reason for this appears to be the low peptide-binding affinity of Ig-derived peptides to major histocompatibility complex (MHC) class I molecules and their resulting low immunogenicity. This might be improved by conservative amino acid modifications at the MHC-binding residues of the peptides (heteroclitic peptides). In this study, it was found that in 18 Ig-derived peptides, that heteroclitic peptides from the Ig gene with improved binding to human leukocyte antigen (HLA)-A*0201 can be used to improve CTL responses. Amino acid substitution substantially increased predicted binding affinity, and there was a strong correlation between predicted and actual binding to HLA-A*0201. CTLs generated against the heteroclitic peptide had not only enhanced cytotoxicity against the heteroclitic peptide but also increased killing of antigen-presenting cells pulsed with the native peptide. Surprisingly, no difference was observed in the frequency of T cells detected by MHC class I peptide tetramers after stimulation with the heteroclitic peptide compared with the native peptide. CTLs generated against heteroclitic peptides could kill patients' tumor cells, showing that Ig-derived peptides can be presented by the tumor cell and that the failure to mount an immune response (among other reasons) likely results from the low immunogenicity of the native Ig-derived peptide. These results suggest that heteroclitic Ig-derived peptides can enhance immunogenicity, thereby eliciting immune responses, and that they might be useful tools for enhancing immunotherapy approaches to treating B-cell malignant diseases.

MHC Class I related chain A (MICA), Human Leukocyte Antigen (HLA)-DRB1, HLA-DQB1 genotypes in Turkish patients with ulcerative colitis

2020 ◽  
Vol 45 (5) ◽  
pp. 587-592
Author(s):  
Cigdem Kekik Cinar ◽  
Kadir Demir ◽  
Sonay Temurhan ◽  
Filiz Akyuz ◽  
Binnur Pinarbasi ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Human Leukocyte Antigen ◽  
Mhc Class I ◽  
Patient Group ◽  
Human Leukocyte ◽  
Class I ◽  
Control Group ◽  
Leukocyte Antigen ◽  
Hla Genotypes ◽  
Turkish Patients

AbstractObjectivesWe aimed to determine Human Leukocyte Antigen (HLA)-DRB1, DQB1, and MHC Class I related chain A (MICA) genotypes in patients with ulcerative colitis.MethodsHLA-DRB1, HLA-DQB1, MICA genotyping of patient (n:85) and controls (n:100) were performed by PCR-SSO Luminex (One Lambda genotyping kit).ResultsWe found significantly higher DRB1*01 (p:0.022, OR:0.23, CI:0.06–0.8) and MICA*0002/20/55 (p:0.03, OR:0.53, CI:0.29–0.93) alleles in control group whereas DRB1*14 (p:0.04, OR:2.25, CI:1–5.08), DRB1*15 (p:<0.0001, OR:4.54, CI:2.09–9.88) and MICA*0004 (p:0.01, OR:2.84, CI:1.2–6.7) alleles were higher in patient group.ConclusionsThe present study will inform the MICA and HLA genotypes about the protective (DRB1*01, MICA*0002/20/55) or susceptible (DRB1*14, DRB1*15, MICA*0004) alleles of the disease and helps the literature on Turkish patients with ulcerative colitis.

scholarly journals Prioritization of SARS-CoV-2 epitopes using a pan-HLA and global population inference approach

2020 ◽  
Author(s):  
Katie M. Campbell ◽  
Gabriela Steiner ◽  
Daniel K. Wells ◽  
Antoni Ribas ◽  
Anusha Kalbasi
Keyword(s):  
Binding Affinity ◽  
Vaccine Development ◽  
Human Leukocyte ◽  
Response Assessment ◽  
T Cell Response ◽  
Class I ◽  
Leukocyte Antigen ◽  
Population Inference ◽  
Shiny App ◽  
Global Population

SummarySARS-CoV-2 T cell response assessment and vaccine development may benefit from an approach that considers the global landscape of the human leukocyte antigen (HLA) proteins. We predicted the binding affinity between 9-mer and 15-mer peptides from the SARS-CoV-2 peptidome for 9,360 class I and 8,445 class II HLA alleles, respectively. We identified 368,145 unique combinations of peptide-HLA complexes (pMHCs) with a predicted binding affinity less than 500nM, and observed significant overlap between class I and II predicted pMHCs. Using simulated populations derived from worldwide HLA frequency data, we identified sets of epitopes predicted in at least 90% of the population in 57 countries. We also developed a method to prioritize pMHCs for specific populations. Collectively, this public dataset and accessible user interface (Shiny app: https://rstudio-connect.parkerici.org/content/13/) can be used to explore the SARS-CoV-2 epitope landscape in the context of diverse HLA types across global populations.

scholarly journals Human leukocyte antigen susceptibility map for SARS-CoV-2

2020 ◽  
Author(s):  
Austin Nguyen ◽  
Julianne K. David ◽  
Sean K. Maden ◽  
Mary A. Wood ◽  
Benjamin R. Weeder ◽  
...  
Keyword(s):  
Human Leukocyte Antigen ◽  
Mhc Class I ◽  
Human Leukocyte ◽  
Hla Typing ◽  
Class I ◽  
Susceptibility Map ◽  
Leukocyte Antigen ◽  
Histocompatibility Complex ◽  
Binding Peptides ◽  
Human Coronaviruses

ABSTRACTGenetic variability across the three major histocompatibility complex (MHC) class I genes (human leukocyte antigen [HLA] A, B, and C) may affect susceptibility to and severity of severe acute respiratory syndrome 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19). We execute a comprehensive in silico analysis of viral peptide-MHC class I binding affinity across 145 HLA -A, -B, and -C genotypes for all SARS-CoV-2 peptides. We further explore the potential for cross-protective immunity conferred by prior exposure to four common human coronaviruses. The SARS-CoV-2 proteome is successfully sampled and presented by a diversity of HLA alleles. However, we found that HLA-B*46:01 had the fewest predicted binding peptides for SARS-CoV-2, suggesting individuals with this allele may be particularly vulnerable to COVID-19, as they were previously shown to be for SARS (1). Conversely, we found that HLA-B*15:03 showed the greatest capacity to present highly conserved SARS-CoV-2 peptides that are shared among common human coronaviruses, suggesting it could enable cross-protective T-cell based immunity. Finally, we report global distributions of HLA types with potential epidemiological ramifications in the setting of the current pandemic.IMPORTANCEIndividual genetic variation may help to explain different immune responses to a virus across a population. In particular, understanding how variation in HLA may affect the course of COVID-19 could help identify individuals at higher risk from the disease. HLA typing can be fast and inexpensive. Pairing HLA typing with COVID-19 testing where feasible could improve assessment of viral severity in the population. Following the development of a vaccine against SARS-CoV-2, the virus that causes COVID-19, individuals with high-risk HLA types could be prioritized for vaccination.

Education of human natural killer cells by activating killer cell immunoglobulin-like receptors

Blood ◽  
2010 ◽  
Vol 115 (6) ◽  
pp. 1166-1174 ◽  
Author(s):  
Cyril Fauriat ◽  
Martin A. Ivarsson ◽  
Hans-Gustaf Ljunggren ◽  
Karl-Johan Malmberg ◽  
Jakob Michaëlsson
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Mhc Class I ◽  
Target Cell ◽  
Nk Cell ◽  
Killer Cell ◽  
Human Leukocyte ◽  
Class I ◽  
Leukocyte Antigen ◽  
Human Natural Killer Cells

Abstract Expression of inhibitory killer cell immunoglobulin-like receptors (KIRs) specific for self–major histocompatibility complex (MHC) class I molecules provides an educational signal that generates functional natural killer (NK) cells. However, the effects of activating KIRs specific for self-MHC class I on NK-cell education remain elusive. Here, we provide evidence that the activating receptor KIR2DS1 tunes down the responsiveness of freshly isolated human NK cells to target cell stimulation in donors homozygous for human leukocyte antigen (HLA)–C2, the ligand of KIR2DS1. The tuning was apparent in KIR2DS1+ NK cells lacking expression of inhibitory KIRs and CD94/NKG2A, as well as in KIR2DS1+ NK cells coexpressing the inhibitory MHC class I–specific receptors CD94/NKG2A and KIR2DL3, but not KIR2DL1. However, the tuning of responsiveness was restricted to target cell recognition because KIR2DS1+ NK cells responded well to stimulation with exogenous cytokines. Our results provide the first example of human NK-cell education by an activating KIR and suggest that the education of NK cells via activating KIRs is a mechanism to secure tolerance that complements education via inhibitory KIRs.

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